The invention relates to controllably dissolving a composite.
Controlled release of medication in vivo is the subject of much research. Various methods and release agents have been suggested, tested and marketed. Calcium sulfate has been utilized as filler for bone cavities as it is capable of being spontaneously adsorbed and replaced by bone. Calcium sulfate, formed from the hemihydrate, has been used as a controlled release agent alone for the filling of bone cavities and in combination with additives such as medicaments and pesticides. As a carrier for medicaments, it has been useful in vivo because it is biocompatible and is progressively resorbed by the body, thereby eliminating the need for secondary surgical procedures.
One application for a calcium sulfate controlled release agent is the local delivery of medicaments in vivo. The ideal characteristics of a local medicament delivery system are (1) biodegradability, (2) biocompatibility, (3) prolonged pharmaceutical release (e.g., over a period of at least 4 to 6 weeks), (4) reproducibility, (5) predictable pharmacokinetics, and (6) controllability.
One of the disadvantages to the use of calcium sulfate as a carrier is that, for some medicaments, the medicament is eluted from the calcium sulfate matrix at too rapid of a rate.
In general, the invention features a composite having a controlled rate of dissolution. The composite includes at least two regions, each of which includes a composition that includes calcium sulfate. A first region of the composite exhibits a rate of dissolution that is different from a second region of the composite. These composites are useful for filling bone voids and for delivering calcium and medicaments in vivo for sustained periods of time. In one embodiment, the regions are in the form of layers. In another embodiment, the first region surrounds the second region.
The preferred calcium sulfate is selected from the group consisting of alpha-calcium sulfate hemihydrate, beta-calcium sulfate hemihydrate, calcium sulfate dihydrate prepared from alpha-calcium sulfate hemihydrate, calcium sulfate dihydrate prepared from beta-calcium sulfate hemihydrate, and combinations thereof.
In one embodiment, the first composition further includes a medicament, preferably a medicament selected from the group consisting of tetracycline hydrochloride, vancomycin, tobramycin, gentamicin, cephalosporin, cis-platinum, ifosfamide, methotrexate, doxorubicin hydrochloride, transforming growth factor beta, bone morphogenic protein, demineralized bone matrix (xe2x80x9cDBMxe2x80x9d), basic fibroblast growth factor, platelet-derived growth factor, polypeptide growth factors, lidocaine hydrochloride, bipivacaine hydrochloride, ketorolac tromethamine, or a combination thereof. In another embodiment, the second composition also includes a medicament.
In one embodiment, the first composition includes calcium sulfate dihydrate prepared from alpha-calcium sulfate hemihydrate, and preferably, the second composition includes calcium sulfate dihydrate prepared from beta-calcium sulfate hemihydrate.
Preferred compositions are prepared by contacting with an aqueous liquid an alpha-calcium sulfate hemihydrate having a mean particle size of from about 12 xcexcm to about 23.5 xcexcm. In one embodiment, at least 80% of the alpha-calcium sulfate hemihydrate has a particle size of from about 12 xcexcm to about 22 xcexcm more preferably from about 16 xcexcm to about 22 xcexcm. In preferred composites, from about 0.1% to about 2.0% of the alpha-calcium sulfate hemihydrate has a particle size of less than about 2 xcexcm. In one embodiment, the alpha-calcium sulfate hemihydrate has a density of from about 2.6 to about 2.9 g/cm3. In other embodiments, the alpha-calcium sulfate hemihydrate has a purity greater than 98 wt. % calcium sulfate hemihydrate. The preferred range for the BET surface area of the alpha-calcium sulfate hemihydrate is from about 0.2 m2/g to about 1.0 m2/g.
Preferably the calcium sulfate is prepared from alpha-calcium sulfate hemihydrate having a purity greater than 98 weight % (xe2x80x9cwt. % xe2x80x9d) calcium sulfate hemihydrate, a BET surface area in the range of from about 0.35 m2/g to about 0.9 m2/g, a density in the range of from about 2.73 to about 2.80 g/cm3, and a mean particle size of about 16 xcexcm to about 22 xcexcm. Preferably from about 90 to about 95 wt. % of the alpha-calcium sulfate hemihydrate has a particle size distribution from about 1 xcexcm to about 45 xcexcm.
In one embodiment, the first composition is prepared by contacting with an aqueous liquid calcium sulfate consisting essentially of beta-calcium sulfate hemihydrate having a mean particle size in the range of from about 10 xcexcm to about 15 xcexcm. In other embodiments, the beta-calcium sulfate hemihydrate has a purity greater than 98 wt. % calcium sulfate hemihydrate. The beta-calcium hemihydrate can also have a BET surface area of from about 4.5 m2/g to about 7.5 m2/g, more preferably from about 5 m2/g to about 6 m2/g, and a density of from about 2.5 g/cm3 to about 2.6 g/cm3. In another embodiment, the first composition is prepared by contacting with an aqueous liquid calcium sulfate consisting essentially of beta-calcium sulfate hemihydrate having a purity greater than 98 wt. % calcium sulfate hemihydrate, a BET surface area in the range of from about 4.5 m2/g to about 7.5 m2/g, a density in the range of from about 2.5 g/cm3 to about 2.6 g/cm3, and a mean particle size in the range of from about 13 xcexcm to about 14 xcexcm.
In another aspect, the invention features a method of delivering medicament in vivo. The method includes implanting the above-described composite into a mammal.
The composite of the invention permits the controlled dissolution of regions that include a calcium sulfate composition, as well as the controlled release of additives such as, e.g., medicaments and pesticides.
Other features and advantages of the invention will be apparent form the following description of the preferred embodiments thereof, and from the claims.
The composite includes two regions that exhibit different rates of dissolution with respect to each other. The regions of the composite are macroscopic and can exist in a variety of forms in the composite such as, e.g., layers and geometrical shapes, e.g., spheres. The regions can be continuous or discontinuous, and one or more regions can exist within another region or regions.
The regions consist of compositions that include calcium sulfate and, optionally, an additive. Examples of sources of calcium sulfate suitable for use in preparing the compositions include alpha-calcium sulfate hemihydrate powder, beta-calcium sulfate hemihydrate powder, calcium sulfate dihydrate powder made from calcium sulfate hemihydrate powders including alpha-calcium sulfate hemihydrate and beta-calcium sulfate hemihydrate, and combinations thereof.
A preferred alpha-calcium sulfate hemihydrate powder has a purity greater than 98 wt. % calcium sulfate hemihydrate, a BET surface area of from about 0.2 m2/g to about 1.0 m2/g (preferably from about 0.35 m2/g to about 0.9 m2/g, more preferably from about 0.35 m2/g to about 0.7 m2/g), a density of about 2.6 g/cm3 to about 2.9 g/cm3 (more preferably from about 2.73 g/cm3 to about 2.80 g/cm3), and a mean particle size of from about 12 xcexcm to about 23.5 xcexcm. Preferably from about 0.1% to about 2.0% of the alpha-calcium sulfate hemihydrate has a particle size of less than about 2.0 xcexcm. Preferably at least 80% of the alpha-calcium sulfate hemihydrate has a particle size of from about 12 xcexcm to about 22 xcexcm, more preferably from about 16 xcexcm to about 22 xcexcm.
A preferred beta-calcium sulfate hemihydrate powder has a purity greater than 98 wt. % calcium sulfate hemihydrate, a BET surface area of from about 4.5 m2/g to about 7.5 m2/g (more preferably from about 5 m2/g to about 6 m2/g), a density of from about 2.5 g/cm3 to about 2.6 g/cm3, and a mean particle size of from about 10 xcexcm to about 15 xcexcm (more preferably from about 13 xcexcm to about 14 xcexcm).
The calcium sulfate composition of each region, the combination of regions, and the composite can be selected to achieve a desired rate of elution of one or more additives present in the composite, a desired rate of dissolution of the pellet including its regions, and combinations thereof. The composite can include regions of calcium sulfate prepared from a single form of calcium sulfate (e.g., alpha-calcium sulfate hemihydrate or beta-calcium sulfate hemihydrate powder), or multiple forms of calcium sulfate (e.g., a combination of one or more of alpha-calcium sulfate hemihydrate, beta-calcium sulfate hemihydrate, and the dihydrate prepared from alpha-calcium sulfate hemihydrate and beta-calcium sulfate hemihydrate). One example of a useful composite includes an interior region of calcium sulfate dihydrate prepared from beta-calcium sulfate hemihydrate, and an exterior region surrounding the interior region where the exterior region includes calcium sulfate dihydrate prepared from alpha-calcium sulfate hemihydrate. Another example of a useful composite includes an interior region that includes calcium sulfate dihydrate prepared from alpha-calcium sulfate hemihydrate, and an exterior region surrounding the interior region where the exterior region includes calcium sulfate dihydrate made from beta-calcium sulfate hemihydrate. Other examples of composites include one or more calcium sulfate dihydrate regions prepared from a combination of alpha and beta-calcium sulfate hemihydrate.
One example of a useful calcium sulfate composition that includes a mixture of beta-calcium sulfate hemihydrate powder and alpha-calcium sulfate hemihydrate powder, includes a weight ratio of beta-calcium sulfate hemihydrate powder to alpha-calcium sulfate hemihydrate powder of between 0 and about 3. Narrower ranges of this ratio, e.g., 0 to about 0.11, 0 to about 0.05, and 0 to about 0.02, are also contemplated. When used to carry growth factors, the weight ratio of the beta-calcium sulfate hemihydrate powder to the alpha-calcium sulfate hemihydrate powder may range up to about 3:1.
The composition, a region of the composite, or the composite, itself, can also include additives that are controllably released as the region dissolves. Examples of suitable additives include medicaments and pesticides. Examples of useful medicaments include antibiotics, chemotherapeutic agents, growth factors, and analgesics. Examples of useful antibiotics include tetracycline hydrochloride, vancomycin, cephalosporins, and aminoglycocides such as tobramycin and gentamicin. Examples of chemotherapeutic agents include cis-platinum, ifosfamide, methotrexate, and doxorubicin hydrochloride (Adriamycin(copyright)). Examples of growth factors include transforming growth factor beta (TGF-Beta), bone morphogenic protein (xe2x80x9cBMPxe2x80x9d), demineralized bone matrix (xe2x80x9cDBMxe2x80x9d), basic fibroblast growth factor, platelet-derived growth factor, and other polypeptide growth factors. Examples of analgesics include anesthetics such as lidocaine hydrochloride (Xylocaine(copyright)), bipivacaine hydrochloride (Marcaine(copyright)), and non-steroidal anti-inflammatory drugs such as ketorolac tromethamine (Toradol(copyright)).
The composite can include distinct regions each containing 0 to about 25 wt. % additive, preferably about 2 wt. % to about 10 wt. % additive, most preferably about 2 wt. % to about 5 wt. % additive.
One method of preparing a composite includes preparing two or more regions, and then combining, e.g., through pressure, adhesion or molding, two or more regions to form the composite, e.g., a pellet, a tablet or other geometric shape. The regions can be prepared by combining a source of calcium sulfate with an aqueous liquid to form a calcium sulfate composition, and then molding or applying pressure to the calcium sulfate composition to form the region.
The aqueous liquid can include salt, e.g., sodium chloride, i.e., it may be a saline solution. An alpha- or beta-calcium sulfate hemihydrate powder will convert to the dihydrate form upon contact with water or saline. The water to calcium sulfate weight ratio is preferably in the range of from about 0.22 to about 1, more preferably in the range of from about 0.27 to about 0.35 for alpha-calcium sulfate hemihydrate, and from about 0.65 to about 0.85 for beta-calcium sulfate hemihydrate powder. The consistency of a calcium sulfate powder (i.e., ml solution/grams calcium sulfate) is proportional to its surface area and is dependent upon the morphology of the crystal.
Additives can be incorporated into the composite using a variety of methods including, e.g., incorporating the additive into the calcium sulfate powder mixture (e.g., by mixing the additive with the calcium sulfate in powdered form prior to forming the calcium sulfate and aqueous liquid composition), addition of the additive to the calcium sulfate and aqueous liquid composition, and impregnating the formed region with an additive, e.g., by contacting the region with an additive in the form of a liquid or aerosol. Another useful method for incorporating an additive into the composite includes dissolving or suspending the additive into a solution and subsequently impregnating the additive into the calcium sulfate powder.
The composite can be formulated to provide a predetermined rate of dissolution or rate of release. Factors that influence the rate of dissolution or rate of release of the composite include, e.g., the composition of the composite, the composition of the regions, and the structure of the composite, e.g., the location of the regions within the composite. In addition, the form of calcium sulfate, the number of different forms of calcium sulfate, and the amount of each form of calcium sulfate present in the composition can be selected to provide a region having a desired rate of dissolution.
The composite, or a region of the composite, can be pre-formed for ease of use or custom formulated to meet a specific rate of dissolution, or rate of release or profile, e.g., a release rate or profile specified by a surgeon during the performance of an operation.
The invention will now be further described by way of the following example.